Inclusion Criteria: 

• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) with conventional techniques or as >= 10 mm (>= 1 cm) with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam; baseline imaging must be obtained within 30 days of day 1 of study.
• Patients must have histologically confirmed epithelioid hemangioendothelioma which is metastatic or locally advanced (unresectable), and tumor tissue (paraffin-embedded tissue block or tumor tissue on unstained glass slides) available for fusion fluorescence in situ hybridization (FISH) analysis at Cleveland Clinic; patient tumor tissue stored in pathology archives may be used for fusion FISH; a new biopsy is not mandatory.
• Patients must have evidence of disease progression per RECIST 1.1 prior to enrollment or have evidence of cancer-related pain requiring symptom management with narcotic analgesics.
• Patients previously untreated or treated with drug therapy for epithelioid hemangioendothelioma (EHE) are eligible; there is no limit on the number of prior regimens used to be eligible.
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%).
• Life expectancy of greater than 6 months.
• Able to swallow orally-administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or small bowel.
• All prior treatment-related toxicities must be Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5) grade =< 1 (except alopecia) at the time of enrollment.
• Absolute neutrophil count (ANC) >= 1 x 10^9/L (within 2 weeks of patient registration [for blood results] and 30 days of registration for left ventricular ejection fraction [LVEF] assessment).
• Hemoglobin >= 9 g/dL, patients may receive transfusion to meet criterion (within 2 weeks of patient registration [for blood results] and 30 days of registration for LVEF assessment).
• Platelets >= 75 x 10^9/L (within 2 weeks of patient registration [for blood results] and 30 days of registration for LVEF assessment).
• Albumin >= 2.5 g/dL (within 2 weeks of patient registration [for blood results] and 30 days of registration for LVEF assessment).
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (within 2 weeks of patient registration [for blood results] and 30 days of registration for LVEF assessment);
  • NOTE: patients with elevated bilirubin secondary to Gilbert's disease are eligible to participate in the study.
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional ULN (within 2 weeks of patient registration [for blood results] and 30 days of registration for LVEF assessment).
• Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault formula) >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min (within 2 weeks of patient registration [for blood results] and 30 days of registration for LVEF assessment).
• LVEF >= institutional lower limit of normal (LLN) by echocardiogram (ECHO) or multigated acquisition scan (MUGA) (within 2 weeks of patient registration [for blood results] and 30 days of registration for LVEF assessment).
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, during the study participation, and for four months after the last dose of the drug; women of child-bearing potential must have a negative serum pregnancy test within 14 days prior to enrollment and agree to use effective contraception throughout the treatment period and for 4 months after the last dose of study treatment; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
• Human immunodeficiency virus (HIV)-patients positive for human immunodeficiency virus (HIV) are NOT excluded from this study, however HIV-positive patients must meet the following criteria:
  • A stable regimen of highly active anti-retroviral therapy (HAART).
  • No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections.
  • A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard polymerase chain reaction (PCR)-based test.

Exclusion Criteria:

• Prior systemic therapy with a MEK inhibitor.
• History of another malignancy.
• Exception: patients who have been disease-free for 3 years or patients with a history of completely resected non-melanoma skin cancer and/or patients with indolent secondary malignancies, are eligible; consult the Cancer Therapy Evaluation Program (CTEP) medical monitor if unsure whether second malignancies meet the requirements specified above.
• History of interstitial lung disease or pneumonitis requiring supplemental oxygen or treatment with oral or intravenously administered corticosteroids.
• Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity (e.g., doxorubicin), biologic therapy, or immunotherapy within 21 days prior to enrollment and/or daily or weekly chemotherapy (e.g., sunitinib, sorafenib and pazopanib) without the potential for delayed toxicity within 14 days prior to enrollment.
• Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of trametinib and during the study.
• Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression.
• Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trametinib, or excipients or to dimethyl sulfoxide (DMSO).
• Current use of a prohibited medication; the following medications or non-drug therapies are prohibited:
  • Other anti-cancer therapy while on study treatment; (note: megestrol [Megace] if used as an appetite stimulant is allowed).
  • Concurrent treatment with bisphosphonates is permitted; however, treatment must be initiated prior to the first dose of study therapy; prophylactic use of bisphosphonates in patients without bone disease is not permitted, except for the treatment of osteoporosis.
  • Because the composition, PK, and metabolism of many herbal supplements are unknown, the concurrent use of all herbal supplements is prohibited during the study (including, but not limited to, St. John’s wort, kava, ephedra [ma huang], ginkgo biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or ginseng).
• The concurrent use of all herbal supplements is prohibited during the study (including, but not limited to, St. John's wort, kava, ephedra [ma huang], ginkgo biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or ginseng).
• History or current evidence/risk of retinal vein occlusion (RVO).
• History or evidence of cardiovascular risk including any of the following: 
• A QT interval corrected for heart rate using the Bazett's formula QTcB >= 480 msec. 
• History or evidence of current clinically significant uncontrolled arrhythmias (exception: patients with controlled atrial fibrillation for > 30 days prior to randomization are eligible). 
• History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization. 
• History or evidence of current >= class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system. 
• Treatment-refractory hypertension defined as a blood pressure of systolic >140 mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive therapy.
• Patients with intra-cardiac defibrillators .
• Known cardiac metastases.
• Known hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (patients with chronic or cleared HBV and HCV infection are eligible). 
• Any serious and/or unstable pre-existing medical disorder (aside from malignancy exception above), psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures.
• The study drug must not be administered to pregnant women or nursing mothers; women of childbearing potential should be advised to avoid pregnancy and use effective methods of contraception; men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception; if a female patient or a female partner of a patient becomes pregnant while the patient receives trametinib, the potential hazard to the fetus should be explained to the patient and partner (as applicable).
• Inability to comply with protocol-required procedures.